A. Field of the Invention
The present invention pertains to the field of complex metal chelate chemistry and, more specifically, to a method whereby complex metal chelates are labeled, or "tagged", with a radioactive metal isotope through a mechanism whereby isotopic exchange occurs between the complex metal chelate and an "activated" radioactive metal isotope.
The labeled complex metal chelate compounds prepared in accordance with the present invention are useful in various applications which utilize the presence of a radioactive isotope in the complex metal chelate compound. One area employing such application is the field of medical diagnosis of pernicious anemia and other malabsorption states. Vitamin B.sub.12, (hereinafter also referred to as "cyanocobalamin"), is one such complex metal chelate compound which can be labeled with a radioactive metal isotope, such as .sup.57 Co.sup.+.sup.2, in accordance with the present invention. Vitamin B.sub.12 is itself useful as a preventative for pernicious anemia and, when labeled with a radioactive isotope, its presence, or absence may be readily detected throughout the body, thus facilitating the diagnosis of abnormalities effecting its use thereby.
Furthermore, various radioactively labeled complex metal chelate compounds are being evaluated as chemotheraputic agents for the localized treatment of cancer by irradiation, for example cancer of the liver. There are other useful medical applications requiring "tagged" complex metal chelate compounds which, by virtue of their radioactivity, can be easily detected, or traced, in living organisms.
B. Description of the Prior Art
Complex metal chelate compounds containing radioactive metal isotopes have been known and utilized in the prior art. For example, "tagged" Vitamin B.sub.12, that is Vitamin B.sub.12 containing a radioactive isotope of cobalt, has been used in the diagnosis of pernicious anemia and has been prepared via biochemical synthesis, wherein microbes are cultured in the presence of a cobalt-57 salt and produce Vitamin B.sub.12 containing cobalt-57 isotopes which must then be purified by lengthy chromotographic separations. However, numerous attempts to label Vitamin B.sub.12 by isotopic exchange in solution have been unsuccessful; see R. N. Booc, et al., "The Exchange Stability of Cobalt in Vitamin B.sub.12 ", 73 J. Amer. Chem. Soc. 5446 (1951); and R. A. Baldwin, et al., "The Failure to Crystalline Vitamin B.sub.12 to Exchange with Cobalt-60 in Acidic and Neutral Aqueous Solutions"; 73 J. Amer. Chem. Soc. 4968 (1951).
Isotopic exchange between a radioactive metal isotope in a complex metal chelate takes place in solution only for chelates with labile ligands. In complex metal chelates in which the metal atoms exist in a higher oxidation state, the ligands are very strongly bound to the central metal atoms. However, in complex metal chelates in which the metal exists in a lower redox state, the ligands are more labile, i.e. the cobalt is not as strongly bound to the ligand and theoretically is more susceptible to isotopic exchange with a radioactive metal isotope, provided that sufficient energy is imparted to "activate" the radioactive metal isotope.
For example, in complex Cobalt (III) chelates, the ligands are very strongly bound to the central cobalt atom and, therefore, isotopic exchange is very difficult to achieve. However, complex Cobalt (II) chelates have much more labile ligands and, accordingly, should be much more susceptible to isotopic exchange with an activated radioactive metal isotope. In practice, however, attempts in the past, such as those made by Diehl and Voigt, "The Failure of Exchange Between Vitamin B.sub.12r and Radioactive Cobalt Chloride", 32 Iowa State J. of Science 4 (1958), have been unsuccessful. Voigt and his co-workers tried unsuccessfully to exchange .sup.60 Co.sup.+.sup.2 with the central cobalt atom of Vitamin B.sub.12r in solution. Apparently, it was thought that the cobalt atom in Vitamin B.sub.12r was still too strongly bonded to the ligands for isotopic exchange to occur.
Attempts have also been made to achieve isotopic exchange for complex metal chelates in the solid state. These attempts have met with some success, but have not provided a method of labeling complex metal chelate compounds with a radioactive metal isotope having the advantages of the novel method of the present invention.
One such solid state method was that used by Nath, et al, "Isotopic Exchange in the Solid State and Thermal Annealing of Recoil Damage in cobalt Complexes: A New Model", Vol. 4. No 2 Indian J. of Chem. 51-56 (1966), which was unsuccessful in effecting noticeable isotopic exchange in cyanocobalamin. That method involved heating of a mixture of the cyanocobalamin and .sup.60 Co.sup.+.sup.2 activity to about 180.degree.C in a vacuum. The cobalt complexes which were found to undergo isotopic exchange in the solid state, such as tris-dipyridyl Cobalt (III) perchlorate, were much simpler compounds than the complex metal chelates of the present invention. Furthermore, it was noted that in accordance with the prior art method of Nath et al., the rate of exchange was considerably retarded by the presence of oxygen.
Therefore, while radioactively labeled complex metal chelate compounds had been known in the prior art, the methods used to label these compounds have not been able to satisfactorily supply the compounds efficiently and economically. Furthermore, the prior art methods have been unable to produce many of the labeled complex metal chelate compounds of the present invention.